tbuckley/cabot-search huggingface dataset:
OTHR-02. CHIMERIC AURORA A KINASE (AURKA) DEGRADERS EFFICIENTLY TARGET N-MYC
Authors: Gintvile Valinciute, Lorenz Eing, Jeffrey Mihalic, Colleen E Casey, Hua Tian, Bikash Adhikari, Cristiana Guiducci, Ryan Rountree, Christoph Grohmann, Sangita Sridharan, Ya-Wen Lu, Simon Vezina-Dawod, Eric Wegrzyniak, Abhinav Chaterjee, Gwenn M Hansen, John M Maris, Yael P Mossé, Martin Eilers, Elmar Wolf, Martine F Roussel
Journal: Neuro-Oncology (2023)

Abstract MYC family proteins are primary drivers of oncogenic processes in a variety of cancer histologies. N-myc overexpression and amplification induce aggressive pediatric cancers, the most common of which are solid extracranial tumors in children (neuroblastoma, NB) and malignant pediatric CNS tumors (medulloblastoma, MB). Due to the oncogenic addiction observed in these tumor types, N-myc is considered an attractive therapeutic target. However, direct small molecule targeting of N-myc remains technically challenging. Alternative approaches to target this pathway include inhibiting proteins thought to stabilize N-myc, such as Aurora A kinase (AURKA). While inhibition of AURKA was found to be effective in preclinical tumor studies, no AURKA inhibitors have been approved for clinical use due to a lack of efficacy. Here, we aim to develop chimeric degrader molecules suitable for preclinical and clinical use that degrade AURKA and concomitantly reduce N-myc levels. We used automated solid-phase synthesis to generate a library of &amp;gt;1000 chimeric degraders using derivatives of six known AURKA ligands (Series 1-6). Due to the limitations of using N-myc-driven MB cells in vitro, we employed NB cells as the proof-of-concept model. While the degraders based on five of the ligands showed efficient AURKA degradation, only degraders based on series 3 and 6 could also diminish N-myc. Selected series were further characterized in pharmacokinetic and pharmacodynamic experiments using NB tumor xenografts implanted in the flank in CD1-nude mice. In summary, chimeric degraders based on two individual AURKA ligands efficiently degraded AURKA and N-myc in vitro and in vivo, providing the foundation for further development of novel therapies for patients with N-myc-driven cancers. Further studies will focus on assessing antitumor properties of lead candidates in NB and patient-derived orthotopic MB xenograft models.
HGG-11. APPLICATION OF SHUNT IN PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA COMPLICATED WITH HYDROCEPHALUS: A 10-YEAR EXPERIENCE FROM A SINGLE CENTER
Authors: Linbo Cai, Mingyao Lai, Juan Li, Ruyu Ai
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE Currently, there is no unified treatment protocol for pediatric diffuse intrinsic pontine glioma with hydrocephalus. The present study aims to explore the clinical characteristics and the best intervention modality for pediatric diffuse intrinsic pontine glioma with hydrocephalus. METHODS The detailed data of children with diffuse intrinsic pontine glioma admitted to the Department of Pediatrics of Guangdong Sanjiu Brain Hospital from January 2010 to December 2021 were retrospectively analyzed. The effect of radiotherapy and shunt on the prognosis of pediatric diffuse intrinsic pontine glioma complicated with hydrocephalus was evaluated. RESULTS 165 children with DIPG aged ≤18 years were included in the analysis, of whom 9 (5.5%) had mild ventricular dilatation, 48 (35%) had hydrocephalus, and 11 (22.9%) underwent cerebrospinal fluid shunting, of whom 10 (90.9%) underwent ventriculoperitoneal shunt and 1 (9.1%) underwent endoscopic third ventriculostomy. After shunt and radiotherapy, 53 cases of hydrocephalus could be evaluated, of which 37 patients (69.8%) were significantly relieved, and 16 (30.2%) were not. 99 children had tumor progression after treatment, including 41 cases (41.4%) with hydrocephalus and 5 cases (12.2%) with ventriculoperitoneal shunt. A total of 138 children were included in the survival analysis, which revealed that hydrocephalus, mild ventricular dilatation, and no ventricular abnormality had no effect on the prognosis (p=0.944). The treatment of hydrocephalus at the initial diagnosis did not affect the prognosis, p=0.405. The median survival of the hydrocephalus remission group post-radiotherapy was 12 months, and 8 months for the non-remission group, p=0.042. The median survival was 20 months in the shunt group and 8 months in the untreated group (p=0.005). CONCLUSIONS Asymptomatic ventricular enlargement in pediatric diffuse intrinsic pontine gliomas does not require surgical intervention. Hydrocephalus remission post-radiotherapy is a favorable prognostic indicator. Cerebrospinal fluid shunt could improve the prognosis of children with hydrocephalus when the tumor progresses post-radiotherapy.
LGG-02. DRUG-CLASS SPECIFIC GENE-BASED MAPK SENSITIVITY SCORES (MSS) PREDICT SENSITIVITY TO MAPK INHIBITORS AND IDENTIFY IMMUNE INFILTRATION AS PUTATIVE TARGET IN PEDIATRIC LOW-GRADE GLIOMAS
Authors: Romain Sigaud, Thomas K Albert, Caroline Heß, Thomas Hielscher, Nadine Winkler, Carolin Walter, Daniel Münter, Florian Selt, Diren Usta, Jonas Ecker, Angela Brentrup, Martin Hasselblatt, Christian Thomas, Julian Varghese, David Capper, Ulrich W Thomale, Pablo Hernáiz Driever, Michèle Simon, Svea Horn, Nina Annika Herz, Arend Koch, Felix Sahm, Stefan Hamelmann, Augusto Faria Andrade, Nada Jabado, Antoinette Y N Schouten-van Meeteren, Eelco Hoving, Tilman Brummer, Cornelis M van Tilburg, Stefan M Pfister, Olaf Witt, David T W Jones, Kornelius Kerl, Till Milde
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Pediatric low-grade gliomas (pLGG), the most common brain tumors in children, are driven by alterations in the MAPK pathway. Several clinical trials have shown the potential for MAPK inhibitors (MAPKi) treatment in pLGG. However, the range of response is broad, even within entities sharing the same driving genetic MAPK alteration. A predictive stratification tool is needed to identify patients that will be more likely to benefit from MAPKi therapy. METHODS We generated gene-expression-based MAPKi sensitivity scores (MSS) for each MAPKi class (BRAFi, MEKi, ERKi), based on MAPK-related genes differentially regulated between MAPKi sensitive and non-sensitive cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) dataset. Single sample Gene Set Enrichment Analysis (ssGSEA) was used to measure and validate our MSSs in the GDSC dataset and an independent PDX dataset (XevaDB). The validated signatures were tested in a pLGG-specific background, using gene expression data from PA cell lines and primary pLGG samples. RESULTS Our MSS could differentiate MAPKi sensitive cells in the GDSC dataset, and significantly correlated with MAPKi response in the XevaDB PDX dataset. The MSS were able to differentiate glioma entities with differing MAPK alterations from non-MAPK altered entities, and showed the highest scores in pLGG. The MSSs were heterogeneous within pLGG entities with a common MAPK alteration, as observed in MAPKi clinical studies. Intriguingly, a strong correlation between our MSS and the predicted immune cell infiltration rate, as determined by the Estimate score, was observed and confirmed in a pLGG scRNA sequencing dataset. CONCLUSION These data demonstrate the relevance of gene-expression signatures to predict response to MAPKi treatment in pLGG, and will be further investigated in a prospective manner in upcoming clinical trials. In addition, our data could suggest a role of immune infiltration in the response to MAPKi in pLGG that warrants further validation.
OTHR-04. DEVELOPMENT OF A FUNCTIONAL PLATFORM FOR REAL-TIME PERSONALIZED DRUG SENSITIVITY PROFILING OF PATIENT-DERIVED 3D FRESH TUMOR TISSUE CULTURES IN THE PEDIATRIC PRECISION ONCOLOGY PROGRAM INFORM
Authors: Heike Peterziel, Nora Jamaladdin, Dina ElHarouni, Xenia F Gerloff, Sonja Herter, Petra Fiesel, Yannick Berker, Mirjam Blattner-Johnson, Kathrin Schramm, Barbara C Jones, David Reuss, Laura Turunen, Aileen Friedenauer, Tim Holland-Letz, Martin Sill, Lena Weiser, Christopher Previti, Gnanaprakash Balasubramanian, Nicolas U Gerber, Johannes Gojo, Caroline Hutter, Ingrid Øra, Olli Lohi, Antonis Kattamis, Bram de Wilde, Frank Westermann, Stephan Tippelt, Norbert Graf, Michaela Nathrath, Monika Sparber-Sauer, Astrid Sehested, Christof M Kramm, Uta Dirksen, Olli Kallioniemi, Stefan M Pfister, Cornelis M van Tilburg, David T W Jones, Jani Saarela, Vilja Pietiäinen, Natalie Jäger, Matthias Schlesner, Annette Kopp-Schneider, Sina Oppermann, Till Milde, Olaf Witt, Ina Oehme
Journal: Neuro-Oncology (2023)

Abstract The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75-78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs.
DIPG-46. TARGETING THE METABOLIC ERK5-PFKFB3 AXIS IN PEDIATRIC DIFFUSE MIDLINE GLIOMA
Authors: Stephanie Casillo, Taylor Gatesman, Akanksha Chilukuri, Esther Jane, Daniel Premkumar, Callie Barber, Matthew Halbert, Andrea Cruz, Steven Mullett, Joshua Michel, Yue-Fang Chang, Antony MichaelRaj, Frank Lieberman, James Felker, Sruti Shiva, Kalil Abdullah, Pascal Zinn, Robert Friedlander, Taylor Abel, Sriram Venneti, Stephen Mack, Stacy Wendell, Ian Pollack, Sameer Agnihotri
Journal: Neuro-Oncology (2023)

Abstract Diffuse midline glioma is an aggressive brain tumor with a median age at diagnosis of 6.3 years and 5-year survival rate of 2.2%.The defining histone mutation H3K27M precludes docking of a protein responsible for epigenetic modification resulting in erroneously accessible chromatin and subsequent transcription of oncogenic pathways, including the RAS-MERK5-ERK5 signaling cascade. To determine which oncogenic processes are regulated by extracellular signal-regulated kinase 5 (ERK5), gene-set enrichment analysis of patient-derived datasets demonstrated gene networks involved in glycolysis to be enriched with ERK5 expression. In confirmation, loss of ERK5 via shRNA interference reduced cell proliferation and glycolysis in DIPG IV and SF8628 cells. Reintroduction of ERK5 wildtype (WT) into ERK5 knockdown lines rescued cell proliferation and glycolysis, while the addition of ERK5 kinase dead domain (KDD) only partially rescued these survival and metabolic defects. Targeted evaluation of glycolysis enzyme expression via qRT-PCR revealed a direct relationship between ERK5 and proglycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Mechanistically, ERK5 activation of PFKFB3 was mediated by activation of transcriptional factor myocyte enhancer factor 2A (MEF2A) as demonstrated by coimmunoprecipitation and luciferase promoter assays. Expression of PFKFB3 was elevated at both the mRNA and protein level in DMG patient-derived samples. Genetic knockdown of PFKFB3 via shRNA interference resulted in reduced proliferation and glycolysis in DIPG IV and SF8628 cells. Similarly, pharmacologic inhibition of PFKFB3 with small molecule inhibitor PFK-158 capitulated these results. This inhibitor demonstrated blood brain barrier penetrance in silico and extended survival of in vivo mouse models. Multitargeted drug therapy against both ERK5 and PFKFB3 produced a synergetic in vitro response with increased sensitivity of these cells to apoptosis compared to single treatment alone. In conclusion, these results support ERK5 regulation of glycolysis through the critical metabolic effector PFKFB3. Multitargeted drug therapy against this axis represents a therapeutic vulnerability in pediatric diffuse midline glioma.
IMMU-19. NIVOLUMAB-INDUCED CNS DEMYELINATION IN A 15-YEAR-OLD WITH CLASSIC HODGKIN LYMPHOMA
Authors: Alejandra Ramirez, Alexander Jonokuchi, Nobuko Hijiya, William Gomes, Sarah Wesley, Gurcharanjeet Kaur
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Nivolumab associated neurologic immune-related adverse events (irAEs) have been reported in less than 1% of patients and mainly in the adult population. Here we present a pediatric case of nivolumab related CNS demyelination. Case description: 15-year-old male with nodular sclerosis stage III classic Hodgkin lymphoma was enrolled to receive chemotherapy following SWOG S1826 protocol. Eight weeks after the first dose of nivolumab, he had a single episode of seizure. Prolonged EEG showed no epileptiform discharges. Levetiracetam was initiated. Initial MRI showed a non-enhancing T2 hyperintense focal cortical thickening in the left primary motor cortex. CSF studies were significant for mild lymphocytic pleocytosis. One dose of nivolumab was held with subsequent doses given. Levetiracetam was continued and follow-up EEGs were normal. Repeat MRI done three months later showed multiple new parenchymal hyperintense lesions including in the anterior temporal lobe with central curvilinear enhancement, and faintly enhancing lesions in the left fusiform gyrus, juxtacortical white matter of the right middle temporal gyrus, and left superior cerebellar peduncle, findings consistent with CNS demyelination. At this time, CSF showed 9 WBCs (94% lymphocytes) and oligoclonal bands with negative cytology and flow cytometry making CNS lymphoma highly unlikely. The last two doses of nivolumab were held and he was started on methylprednisolone. The most recent MRI ten weeks after the last dose of nivolumab showed resolution of the abnormal findings. DISCUSSION There is limited published literature about neurologic complications of immune checkpoint inhibitors (ICPis) in the pediatric population. CNS demyelination and other neurologic irAEs should be suspected in patients presenting with new neurologic symptoms who started any ICPi within the past three months and after other causes including disease progression, metastasis, metabolic or infectious disorders have been ruled out. Treatment varies depending on severity but includes discontinuation of the ICPi and steroids.
MDB-09. IMPACT OF PRDM6 ON CHROMATIN ACCESSIBILITY, GENE EXPRESSION, AND MEDULLOBLASTOMA FORMATION
Authors: Christin Schmidt, Sarah Husain, Annika Carlson, Sarah Cohen, Samantha Westelman, Linyu Wang, William Weiss, Bjoern Schwer
Journal: Neuro-Oncology (2023)

Abstract Group 4 medulloblastoma (MB) is the most common medulloblastoma subgroup and shows high incidence of metastasis and late-onset relapse cases. These tumors lack a unifying oncogenic driver and treatment targets, despite extensive genomic characterization. Group 4 MBs are characterized by recurrent genetic alterations in chromatin modifiers and amplification of stemness genes. A substantial fraction of Group 4 MBs are characterized by enhancer hijacking through tandem duplication of SNCAIP, resulting in high expression of PRDM6, a putative transcriptional repressor and histone methyltransferase. Some PRDM6-overexpressing medulloblastoma cases show additional mutations in chromatin regulators and high MYCN expression. We set out to elucidate the impact and oncogenic potential of sustained PRDM6 expression in early neural stem cell populations and patient-derived medulloblastoma cells. We find that PRDM6 expression in human iPSC-derived neuroepithelial stem cells (NESCs) results in tumor growth in mice at low penetrance. Moreover, we find that PRDM6 expression in MYCN-overexpressing NESCs does not further alter tumor aggressiveness or survival in vivo. Notably, PRDM6 overexpression in the patient-derived Group 3 MYC-amplified D283-Med cell line causes significantly increased aggressiveness of tumor growth and shorter survival in mice. At the cellular level, PRDM6 localizes to the nucleus, suggesting a role in gene expression regulation. Consistent with this notion, ATAC-seq and RNA-seq analysis of PRDM6-NESCs and PRDM6-D283-Med cells reveals major changes in chromatin accessibility and gene expression, specifically upregulation of integrin family members and gene family members of focal adhesion and extracellular matrix receptor interaction pathways. We conclude that PRDM6 promotes tumor growth in NESCs and may play a role in tumor maintenance through interactions with the extracellular matrix and tumor microenvironment.
Prognostic and Predictive Markers for Patients With Anal Cancer
Authors: Emma B. Holliday, Arjun Peddireddy, Van K. Morris
Journal: Journal of the National Comprehensive Cancer Network (2023)

Squamous cell carcinoma of the anus and anal canal is a rare malignancy with an increasing incidence in the United States. In the past 2 decades, the proportion of Americans diagnosed with incurable, metastatic anal cancer at the time of initial presentation has increased. Most cases are linked to prior infection with HPV. Although concurrent chemoradiotherapy has been the accepted standard treatment for patients with localized anal cancer over the past half century, therapeutic advances have increased options for patients with unresectable or incurable anal cancer over the past 5 years. Specifically, combination chemotherapy and immunotherapy with anti–PD-(L)1 antibodies has demonstrated efficacy in this setting. Greater understanding of molecular drivers of this viral-associated malignancy has provided critical insight into evolving biomarkers for the clinical management of anal cancer. The pervasiveness of HPV across cases of anal cancer has been leveraged for the development of HPV-specific circulating tumor DNA assays as a sensitive biomarker for prognosticating recurrence in patients with localized anal cancer who complete chemoradiation. For patients with metastatic disease, somatic mutations, well-characterized for anal cancer, have not shown utility in identifying patients who benefit from systemic treatments. Although the overall response rate to immune checkpoint blockade therapies is low for metastatic anal cancer, high immune activation within the tumor and PD-L1 expression may identify patients more likely to experience response. These biomarkers should be incorporated into the design of future clinical trials to personalize further treatment approaches in the evolving management of anal cancer.
Annals Graphic Medicine - Revolving Through Residency
Authors: Rutit Pak
Journal: Annals of Internal Medicine (2023)

Web ExclusivesJune 2023Annals Graphic Medicine - Revolving Through ResidencyFREERutit Pak, DORutit Pak, DODell Medical School at The University of Texas at Austin, Austin, Texas (R.P.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G22-0049 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAuthors: Rutit Pak, DOAffiliations: Dell Medical School at The University of Texas at Austin, Austin, Texas (R.P.)Disclosures: The author has reported no disclosures of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G22-0049.Author/Illustrator Information: Rutit Pak, DO, is an internal medicine resident at The University of Texas at Austin Dell Medical School and a fellow cog in the wheel. Interests include utilizing graphic art and comedy to highlight the struggles of the medical education process (e-mail, rutit.[email protected].org).This article was published at Annals.org on 13 June 2023. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics June 2023Volume 176, Issue 6 ePublished: 13 June 2023 Issue Published: June 2023 Copyright & PermissionsCopyright © 2023 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Real-World Implementation of Best-Evidence Cancer Distress Management: Truly Comprehensive Cancer Care
Authors: Shawna L. Ehlers, Lisa M. Gudenkauf, Elizabeth L. Kacel, Sherrie M. Hanna, Pam S. Sinicrope, Christi A. Patten, Eleshia L. Morrison, Jill Snuggerud, Danielle Bevis, Janae L. Kirsch, Jeffrey P. Staab, Katharine A.R. Price, Andrea E. Wahner-Hendrickson, Kathryn J. Ruddy
Journal: Journal of the National Comprehensive Cancer Network (2023)

Background: Cancer distress management is an evidence-based component of comprehensive cancer care. Group-delivered cognitive behavioral therapy for cancer distress (CBT-C) is the first distress treatment associated with replicated survival advantages in randomized clinical trials. Despite research supporting patient satisfaction, improved outcomes, and reduced costs, CBT-C has not been tested sufficiently within billable clinical settings, profoundly reducing patient access to best-evidence care. This study aimed to adapt and implement manualized CBT-C as a billable clinical service. Patients and Methods: A stakeholder-engaged, mixed-methods, hybrid implementation study design was used, and the study was conducted in 3 phases: (1) stakeholder engagement and adaptation of CBT-C delivery, (2) patient and therapist user testing and adaptation of CBT-C content, and (3) implementation of practice-adapted CBT-C as a billable clinical service focused on evaluation of reach, acceptability, and feasibility across stakeholder perspectives. Results: A total of 40 individuals and 7 interdisciplinary group stakeholders collectively identified 7 primary barriers (eg, number of sessions, workflow concerns, patient geographic distance from center) and 9 facilitators (eg, favorable financial model, emergence of oncology champions). CBT-C adaptations made before implementation included expanding eligibility criteria beyond breast cancer, reducing number of sessions to 5 (10 total hours), eliminating and adding content, and revising language and images. During implementation, 252 patients were eligible; 100 (40%) enrolled in CBT-C (99% covered by insurance). The primary reason for declining enrollment was geographic distance. Of enrollees, 60 (60%) consented to research participation (75% women; 92% white). All research participants completed at least 60% of content (6 of 10 hours), with 98% reporting they would recommend CBT-C to family and friends. Conclusions: CBT-C implementation as a billable clinical service was acceptable and feasible across cancer care stakeholder measures. Future research is needed to replicate acceptability and feasibility results in more diverse patient groups, test effectiveness in clinical settings, and reduce barriers to access via remote delivery platforms.